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Kamandi is the last boy on Earth. Centuries into the future, Earth was brutally transformed by the Great Disaster. Animals mutated into hybrid human forms and became the dominant species on Earth. One remaining human, Buddy Blank, survived and relocated to New York City in an abandoned military bunker called Command-D. He raised his grandson, Kamandi (named after the bunker) and educated him with leftover film reels of Earth's history. Kamandi was fascinated with the past and was inspired to seek out kindred humans.

Blank was attacked and killed by Animal Men soon after. Alone, Kamandi travels the world creating alliances and opposes various tribes of Animal Men, all in hope of one day restoring humanity. He quickly built a reputation that included his exuberance. Kamandi is allied with Dr. Canus, a Dog Man, and Prince Tuftan, of the Tiger Empire.

Kamandi and Dr. Canus encountered Batman who had travelled to the future. Dr. Canus and Batman created a vaccine for a disease that might prevent the Great Disaster. They lead Batman to a time fissure. They suddenly come under attack by Rat Men armed with energy weapons. Batman sets off an exploding Batarang, dropping them into the river, and then attacks the others while Kamandi and Dr. Canus go ahead. Batman slips into the sewers, unaware that another Rat Man is following them underwater. He surfaces to attack Batman and the others aboard their raft, and Kamandi knocks him out. They get to the Statue of Liberty where the time fissure is, and Batman prepares to leave with a vaccine he came to get their help to develop. Batman leaves through the portal and Kamandi and Dr. Canus go to the statue's left nostril where Batman has left a time capsule in their past, his present, for them. The time capsule holds an energy weapon and Kamandi uses it to take out the approaching Rat Men.

They survived the ordeal and later observed the latest military conflict between Ape Men and Tiger Men which was being manipulated by Gorilla Grodd. Fearing for his friend's life, Kamandi entered the battle and saved Tuftan at the cost of revealing his associations. After Batman, Kamandi, and Tuftan led a coalition to defeat the Ape People, the Animal Men's opinion of Kamandi changed for the better.

In a conflict with the mutant Misfit, Kamandi and Dr. Canus decided to gamble on a legendary power source called the 5-5 Module. It was the only thing that could power the device, the Mind Wave Jamming Device, that could defeat Misfit. They went through a wormhole and arrived in 21st century Gotham City.

Misfit and his Servi-Tek robots followed them to the past, however. Batman arrived to offer aid to Kamandi and Canus. After getting blasted into a store, Kamandi discovered the 5-5 Modules, a pack of AA batteries. He threw them to Dr. Canus, who activated the device, a boom box, to defeat Misfit. Unlike Canus, Kamandi was sad to leave the past as he considered it a paradise compared to his era. Misfit soon resurfaced in Tiger City and staged a coup to seize control of the Omega Warhead. Kamandi and Prince Tuftan were defeated when the Joker arrived to aid Misfit.

In the original comic series, a mysterious incident known only as "The Great Disaster" caused the collapse of human civilization. A human boy survived with his grandfather in a bunker called "Command-D". When he dies, the young man — named after the place — sets outs to find more people. What he discovers is that most humans are now primitive and unable to speak, while some animals became humanoid in form and gained human-level intelligence (apparently from the effects of an experiment being carried out shortly before the Disaster). All races were now in a conflict to survive while scavenging among the ruins. Humans were treated as animals, and the animals developed their own civilizations that were suspiciously similar to ancient human ones; e.g., the tigers had a culture like the Roman Empire.